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Sarkar, Sourav. "SYNTHESIS AND STUDY OF ANTI-TUMOR VACCINES." University of Toledo / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1345008057.
Повний текст джерела
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Kärkkäinen, Tiina Sinikka. "Synthesis of glycopeptide-based anti-cancer vaccines." Thesis, University of East Anglia, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273509.
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Haynie, Teron D. "Synthesis of Bacterial Surface Glycans for Conjugate Vaccines." BYU ScholarsArchive, 2020. https://scholarsarchive.byu.edu/etd/8669.
Повний текст джерелаАнотація:
Bacteria are coated with repeating units of oligosaccharides that exhibit remarkable diversity. Often, glycan units of three or even two sugars are sufficient to identify a species of bacteria. Such specificity makes bacterial surface glycans attractive vaccine targets. However, efforts to create effective vaccines against carbohydrates have been hampered by poor vaccine design as well as the human immune tendency to respond to glycan antigens with non-specific, T-cell independent mechanisms. As a result, carbohydrate vaccines have historically produced only adequate memory responses in healthy individuals and poor responses in the elderly or immunocompromised. To circumvent these issues, a novel conjugate vaccine was developed that utilizes theQβ virus-like particle carrier that displays both a carbohydrate antigen as well as a Natural Killer T cell adjuvant. This unique vaccine has been reported to stimulate the production of high affinity (nanomolar) antibodies against carbohydrate antigens. To further conjugate vaccine research, the present work synthesizes two bacterial surface antigens: a trisaccharide from Streptococcus pneumoniae serotype 23F (Sp23F), and a pentasaccharide from Ruminococcus gnavus (Rg). Sp23F has been characterized as one of the more virulent and disease-causing strains of S. pneumoniae. Rg secretes highly immunostimulatory proteins and is associated with irritable bowel syndrome. The Sp23F antigen is synthesized with an alkyne at the reducing end of the sugar to facilitate coupling to Qβ. A selection reagent for Sp23F is also synthesized to enable the extraction of antibodies and B cells that bind the antigen. In conjunction with providing a conjugate vaccine antigen, the Rg pentasaccharide will be examined as a TLR4 ligand and was therefore synthesized without an alkyne. The Rg conjugate vaccine shows promise in treating irritable bowel syndrome as well as facilitating research into the role Rg plays in the human microbiome.
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Karmakar, Partha. "Synthesis and Study of MUC1-Based Anti-tumor Vaccines." University of Toledo / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1449750902.
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Pan, Yanbin. "1. Design and Synthesis of Carbohydrate Cancer Vaccines Based on Biochemical Modification of Cancer Cells 2. Studies on the Total Synthesis of an Antitumor Saponin, OSW-1." online version, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1121130600.
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Hewitt, Michael Charles 1975. "Solution and solid-phase synthesis of potential carbohydrate vaccines for leishmaniasis and malaria." Thesis, Massachusetts Institute of Technology, 2002. http://hdl.handle.net/1721.1/27111.
Повний текст джерелаАнотація:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2002.Vita.
Includes bibliographical references.
The human disease leishmaniasis afflicts over 20 million people worldwide, and is caused by unicellular protozoan parasites. Cell surface carbohydrates are implicated in immune recognition of the parasite by host macrophages. The synthesis of a unique tetrasaccharide found on the parasite cell surface lipophosphoglycan is described. The synthetic material was used to create two novel immungens that are currently being evaluated in an animal model. New methods were also developed for an automated solid-phase synthesis that took a fraction of the time required for the solution-phase synthesis. Malaria kills over 2 million people per year, and is caused by protozoan parasites of the genus Plasmodium. Much of the morbidity and mortality associated with malaria is thought to be due to a toxin released in the host following red blood cell rupture. A glycosylphosphatidylinositol (GPI) anchor of parasite origin was recently identified, and had the properties of a toxin. The synthesis of a modified version of the malarial GPI both in solution and on solid-phase in an automated fashion is described. The synthetic material was attached to a carrier protein and used to immunize mice, who were substantially protected against all aspects of a subsequent challenge by malarial parasites. A new capping protocol for automated solid-phase synthesis is described. A novel fluorous silyl triflate was used to tag deletion sequences that could then be separated from the desired sequence by filtration through fluorous reverse-phase silica gel. Two trisaccharide sequences were synthesized both with and without fluorous capping to demonstrate the effectiveness of the capping protocol.
by Michael Charles Hewitt.
Ph.D.
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Nishat, Sharmeen. "Syntheses and Immunological Evaluation of Zwitterionic Polysaccharide (PS A1) Based Vaccines." University of Toledo / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1470365834.
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Le, Guen Yann. "Synthèse de fragments diversement acétylés des polysaccharides spécifiques des bactéries Shigella flexneri type I." Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCB143.
Повний текст джерелаАнотація:
Shigella flexneri est une entérobactérie Gram négatif responsable de la forme endémique de la shigellose, l’une des quatre causes majeures d’infection diarrhéique chez les jeunes enfants. La cible majeure de la réponse immunitaire lors d’une infection naturelle est le polysaccharide de surface (PS). Chez S. flexneri 1b, l’un des sérotypes prévalents dans les pays en voie de développement, le PS est défini par le pentasaccharide ramifié α-L-rhamnopyranosyl-(1→2)-α-L-rhamnopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→3)-[α-D-glucopyranosyl-(1→4)]-2-acetamido-2-deoxy-β-D-glucopyranoside [I] di-O-acétylé. Ces travaux s’intègrent dans un projet visant le développement d’un vaccin basé sur des sucres synthétiques à couverture large contre les infections par Shigella. Afin de concevoir des glycoconjugués efficaces et induisant une bonne réponse immunitaire chez les enfants, des synthèses multi-grammes des précurseurs mono- à pentasaccharidiques ont été optimisées permettant une stratégie par blocs en vue de l’obtention d’oligosaccharides de grande taille. Au cours de ces synthèses, l’obtention du trisaccharide ramifié C(E)D clé a nécessité de nombreuses optimisations, permettant la conception de synthons tri- à pentasaccharides. Un choix des groupements protecteurs orthogonaux nous a permis d’investiguer les différentes conditions de couplages nous donnant accès à 28 oligosaccharides déprotégés courts diversement acétylés. La validation de ces condensations avec des partenaires plus complexes a permis d’accéder à un large panel d’une cinquantaine d’oligosaccharides de di- à pentadécasaccharides sous leur forme libre, ou encore protégés avec divers degrés d’acétylation700,000 children die each year due to diarrheal diseases, making it the second cause of death among this population. Shigella flexneri is a Gram negative enterobacterium responsible of the endemic form of shigellosis in developing countries. The O-antigen part of the bacterial lipopolysaccharide is the major target of the immune system during natural infection. The O-antigen of S. flexeni 1b, one of the prevalent serotypes, is defined by a ramified pentasaccharide made of three L-rhamnose, one D-glucosamine and one D-glucose with two non-stoichiometric sites for acetylation (I). This work is part of the project aimed at the development of a synthetic carbohydrate-based vaccine against Shigella infections. In order to obtain suitable glyconjugates inducing a high level of protection especially in children, the synthesis of mono- to pentasaccharide precursors was optimized, allowing a convergent synthesis of oligosaccharides with different acetylation patterns. Optimization of the glycosylation conditions, acetylations and protecting group manipulations enable the access to fragments from di to pentadecasaccharides representing S. flexneri type I O-antigen
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Pifferi, Carlo. "Design and synthesis of multivalent glycoconjugates for anti-cancer immunotherapy." Thesis, Université Grenoble Alpes (ComUE), 2017. http://www.theses.fr/2017GREAV060/document.
Повний текст джерелаАнотація:
Le cancer est l’une des principales causes de mort dans le pays développés ; bien que les opérations chirurgicales, la radiothérapie et la chimiothérapie représentent aujourd’hui les principales options de traitement des patients souffrants de tumeurs malignes, leurs effets secondaires sévères ont ouvert la voie au développement de l’immunothérapie antitumorale. A part l’immunothérapie passive, qui est basée sur les anticorps ou tout autre composant du système immunitaire synthétisés en dehors du corps dont la potentielle menace de réactions immunes a été prouvée, nous avons concentré nos efforts sur l’immunothérapie active, qui réside dans la stimulation du système immunitaire du patient pour éradiquer sélectivement les cellules malignes. L’identification d’antigènes carbohydrates associés aux tumeurs (TACAs), surexprimés à la surface des cellules cancéreuses, a permis le développement de vaccins spécifiques à cet antigène. Il est connu depuis plus de 40 ans que la majorité des cancers chez l’homme sont caractérisés par une glycosylation aberrante. Les cellules tumorales peuvent surexprimer des versions tronquées d’oligosaccharides, une séquence terminale inhabituelle ou une augmentation de la sialylation des glycolipides et des glycoprotéines de surface. Un oligosaccharide d’une glycoprotéine tronqué peut rendre une partie de la chaîne principale du peptide, d’habitude caché par le sucre, plus accessible au système immunitaire. Parmi les différents TACAs, nous avons concentré notre attention sur les antigènes Tn et Tf, qui peuvent être trouvés sur des glycoprotéines comme MUC-1, surexprimés sur plus de 90% des carcinomes du sein. Bien que la conception de ces immunomodulateurs repose toujours sur des règles empiriques, il est important de déclencher à la fois la réponse humorale et cellulaire, ainsi qu’un effet de mémoire. Ce défi peut être relevé en combinant, sur une seule molécule, l’antigène carbohydrate exprimés à la surface des tumeurs (épitope des cellules B), les peptides capables de stimuler les cellules CD4+ et CD8+ (épitopes des cellules T) et un adjuvant, pour recueillir tous les éléments du système immunitaire au niveau du site d’injection et renforcer l’absorption des antigènes. De précédentes études faites dans notre groupe de recherche ont publié pour la première fois la synthèse et l’évaluation immunologique d’un prototype de vaccin anticancéreux à quatre composant capable d’induire une réponse immunitaire de longue durée sur des modèles murins. Dans mon travail de thèse, nous avons voulu synthétiser des prototypes de vaccin anticancéreux basés sur les TACAs avec des propriétés immunologiques accrues. Notre stratégie de conception a été guidée par (i) l’importance d’une haute densité de carbohydrates pour promouvoir une capture d’antigène plus efficace et un traitement par les cellules présentatrices d’antigène, et (ii) l’expression hétérogène des TACAs au cours de la maladie et parmi différents patients. En respectant ces deux aspects, il sera possible de déclencher une réponse immunitaire plus forte et à plusieurs facettesCancer is one on the leading causes of death in developed countries; although surgical resection, direct irradiation and cytotoxic chemotherapy represent nowadays the main treatment options for patients suffering with malignancies, their severe side effects paved the way for the rise in popularity of antitumoral immunotherapy. Apart from passive immunotherapy, which is comprised of antibodies or other immune system components that are made outside of the body and has been shown to be associated to potentially life threatening immune reactions, we focused our efforts towards active immunotherapy, which purpose is stimulate the patient immune system to selectively eradicate malignant cells. The identification of tumor-associated carbohydrate antigens (TACAs) on the surface of cancer cells has allowed the development of antigen-specific vaccines. It has been known for over four decades that the majority of human cancers are characterized by aberrant glycosylation. Tumor cells may over-express truncated versions of oligosaccharides, unusual terminal oligosaccharide sequences, or increase sialylation of cell-surface glycolipids and O- and N-linked glycoproteins. A truncated oligosaccharide of a glycoprotein may render a part of the peptide backbone, which is normally shielded by the glycan, more accessible to the immune system. Among the assortment of TACAs we focussed our attention on Tn and TF-antigens, which can be found in membrane-bound glycoproteins like MUC-1, over-expressed in more than 90% of breast carcinomas. Although the design of such immuno-modulators still relies on empiric rules, it is noteworthy important to trigger both humoral and cellular responses, and a memory effect. This challenge can be achieved by combining, within a single molecule, carbohydrate antigen expressed on the surface of tumors (B-cell epitope), peptides capable to stimulate both CD4+ and CD8+ T-cells (T-cell epitopes) and an adjuvant, to gather immune system elements in the injection site and boost the antigen uptake. Previous studies of our research group reported for the first time the synthesis and immunological evaluation of a four-component anticancer vaccine prototype capable of inducing a long-lasting immune response in mice models. In my PhD work we aimed to synthesize TACA-based anticancer vaccine prototypes with improved immunological properties. The principles which guided our design strategies rely on (i) the importance of a high density of carbohydrate epitopes to promote a more effective antigen capture and processing by antigen-presenting cells, and (ii) the evidence of heterogenic expression patterns of TACAs during the course of the disease and among different individuals. Addressing these two aspects would provide a stronger and multifaceted immune response
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Forner, Mar 1980. "Multi-epitope peptide platforms for vaccine applications." Doctoral thesis, TDX (Tesis Doctorals en Xarxa), 2021. http://hdl.handle.net/10803/671028.
Повний текст джерелаАнотація:
Vaccination constitutes one of the most efficient and cost-effective methods of promoting global health. Nevertheless, few vaccines are fully effective, for manifold reasons ranging from intrinsic limitations to more contingent shortcomings related, e.g., to cold chain transport, handling and storage. In this context, peptide-based vaccines that consist of a fully synthetic approach mimicking B-and T-cell epitopes have emerged as an attractive alternative to overcome many such issues. Unfortunately, short peptides have generally been related to low immunogenicity and weak protection. In this thesis, we continue the progress towards the development of efficient peptide vaccines against foot-and-mouth disease (FMD) –a highly contagious viral disease of livestock that has a major economic impact. Particularly, the protective immune response under different conditions (dose, duration, different T-cell epitopes and novel candidates) is assessed in animal models. Moreover, we report the chemical synthesis of higher polyvalent peptide dendrimers using “click” chemistry methods of chemoselective ligation.La vacunació constitueix un dels mètodes més eficients i rendibles per promoure la salut mundial. No obstant això, poques vacunes són plenament efectives, per diverses raons que van des de limitacions intrínseques a deficiències més contingents relacionades, per exemple, amb el transport, manipulació i/o emmagatzematge en cadena de fred. En aquest context, les vacunes basades en pèptids, que plantegen un enfocament totalment sintètic en la reproducció d’epítops de cèl·lules B i T, han sorgit com una alternativa atractiva per superar molts d’aquests problemes. Malauradament, els pèptids lineals i curts s’han relacionat generalment amb baixa immunogenicitat i baixa protecció. En aquesta tesi continuem avançant cap al desenvolupament de vacunes peptídiques eficaces contra la febre aftosa, una malaltia vírica del bestiar altament contagiosa i amb important impacte econòmic. En particular, hem avaluat la resposta immune sota diverses condicions (dosi, durada, diferents epítops de cèl·lules T i nous candidats) en models animals. A més, també hem desenvolupat la síntesi de pèptids multivalents utilitzant reaccions de lligament quimioselectiu amb la coneguda química “click”.
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Beena, T. K. "Antigenic Determinants Of Chicken Riboflavin Carrier Protein: Structural And Functional Aspects." Thesis, Indian Institute of Science, 1994. http://hdl.handle.net/2005/141.
Повний текст джерелаАнотація:
Investigations detailed in this thesis constitute a part of the continuing programme of research undertaken in our laboratory on the riboflavin carrier protein (RCP) with particular reference to identification and synthesis of neutralizing antigenic determinants, design of relevant epitope mimetics with improved immunogenic characteristics and relationship between their secondary structures and immunological properties.
The riboflavin carrier protein is elaborated as a reproductive stratagem to ensure adequate vitamin deposition in the developing oocyte in the chickens. The protein is scrupulously conserved through evolution in terms of physico chemical and immunological characteristics from fish through birds to mammals, including primates. In rodents and subhuman primates immunization with the heteroantigen viz., chicken egg white RCP leads to functional neutralization of the endogenous maternal protein resulting in curtailment of early pregnancy. Thus, the crucial role of RCP in maintenance of pregnancy is established and the protein identified as a potential candidate vaccine for immimocontraception. Further studies with the reduced and carboxymethylated (RCM) RCP as the immunogen reveal that antibodies induced by RCM-RCP are equally effective in bioneutralization of the endogenous protein. So it can be surmised that the native folded structure of RCP is not obligatory for eliciting bioneutralizing antibodies. In an attempt to identify functionally relevant regions of the protein, a panel of monoclonal antibodies (MAbs) have been raised and characterized. One of the MAbs viz., 6J32Ci2 could bring about early fetal resorp-tion when injected to mice with confirmed pregnancies. These results prompted a detail molecular immunological approach to understand underlying mechanisms. The principal aims of the present investigations include: (1) identification of neutralizing epitopes; (2) synthesis of peptidyl sequences incorporating these determinants; (3) an understanding of the structure, antigenic and immunogenic characteristics of these peptides; (4) correlation of conformational and antigenic characteristics; (5) rational design and synthesis of peptide analogs with greater propensity to assume predicted secondary structures; (6) analysis of conformation dependency of peptide antigens and the importance of such conformation in generating an optimal B-cell response; (7) the efficacy of the antibodies elicited by these Peptide antigens in neutralizing endogenous protein with the ultimate aim of designing synthetic vaccines.
Chapter 1 of this thesis deals with a general introduction summarizing the current status of knowledge regarding the chemistry and biology of RCP as well as synthetic peptides as potential immunogens. Chapter 2 outlines details of the experimental procedures adopted. Chapter 3 describes the results of investigations on the C-terminal fragment (residues 200-219) of cRCR The main consideration in selecting this sequence for the design of a potential peptide-based vaccine relied on the epitopic specificity of the neutralizing MAb 6S2C12. Epitope mapping using the Pepscan method revealed that the monoclonal antibody recognizes a core sequence corresponding to residues 203-210 of the cRCP. A 21-residue synthetic peptide (C-21) comprising this epitope was synthesized and antibodies elicited to the peptide conjugated to two different carriers, namely diphtheria toxoid and purified protein derivative (PPD) for T-cell help. In both active and passive immunoneutralization experiments, the peptide specific neutralizing antibodies interfered with the biological function of the protein and hence either protected from pregnancy or caused early fetal resorption in rodents as well as in sub-human primates. The conforma-tional properties of the peptide in aqueous buffers were analyzed from circular dichroism which revealed the absence of any ordered structure in the native C-21 peptide. Theoretical predictions of secondary structure suggested a propensity for an t*-helical structure for this fragment in the native protein. Therefore, influence of the helix-promoting solvent, vizM 2,2,2,trifluroethanol (TFE) on the C-21 peptide was investigated. Addition of TFE resulted in spectral changes with negative bands at 208 and 222 nm and a positive band at 190 rim which are typical of an a-helix.
To gain more information on the conformational characteristics of this peptide, it was considered worthwhile to stabilize the native peptide in an a-helical conformation based on simple rational design principles. Towards this end, four analogs of the parent peptide were synthesized and helix stabilization was sought to be achieved by introducing either salt bridges or back-bone conformational constraints such as by incorporating a-amino isobutyric acid at appropriate positions. In all the analogs, the core sequence, recognised by the neutralizing MAb 6B2C12 was maintained intact to ensure induction of antibodies capable of recognizing the native protein. CD spectral analysis of the analog peptides indicated that all the engineered peptides had varying degrees of enhanced helicities as compared to the parent peptide. The immunogenicity of each analog was studied by to the relevant peptide-diphtheria toxoid conjugates and analyzing their reactivities with the native protein by direct and competitive ELISA. The results revealed that these engineered conformational analogs axe highly immunogenic eliciting high titers of anti-protein antibodies. The relative affinities of these antibodies to bind cRCP were investigated. The antibodies to peptide analogs had higher affinities for the native protein and a positive correlation was found between the helical content of the peptide antigen in question and the relative affinity of corresponding antibody. The antibodies directed to all the peptide analogs could block the function of RCP resulting in early embryonic resorption when administered to pregnant mice. An interesting pattern of immunological cross-reactivity has been observed with the native and designed peptides. Antibodies raised to constrained helical analogs could bind the C-21 peptide which is structurally flexible. In contrast, the antibodies raised to the flexible native peptide antigen were inefficient in recognizing the structured peptides. The ability of all the peptide antibody to bind the native protein has been interpreted in terms of a conformationally flexible C-terminus region in cRCP.
Chapter 4 details investigations on a 21-residue peptide (N- 21) from the N-terminiis (4-24) of the protein. Selection of this peptidyl sequence relied on theoretical prediction of potential sequential determinants on RCP other than at C-terminus as well as on the outcome of immunoneutralisation experiments using antibodies to egg yolk RCP which lacks the relevant C-terminal determinants. The structure of this peptide in solution was analyzed by two dimensional NMR and CD. NMR experiments revealed the presence of two structured regions in the peptide. Diagnostic nuclear Overhauser effects characteristics of reverse turns or short frayed helical segments over residues 3-9 and 18-21 of the peptide were obtained. CD spectra showed the presence of a strong, negative band at 204 nm over a wide range of solvent conditions, a feature which has been interpreted in terms of a "polyproline Il-like" segment encompassing residues 11-16 which corresponds to an interesting (X-Pro)^ repeat in the N-21 sequence.
Specific antibodies were generated to this peptide as a conjugate with diphtheria toxoid. Administration of the antipeptide antibodies could neutralize the protein in vivo as demonstrated by early embryonic loss in pregnant mice. In limited experiments the antipeptide antibodies showed propensity to protect bonnet monkeys from pregnancy over a few consecutive ovulatory cycles when titres are maintained elevated by periodic boosting. To address the relationship between peptide structures and antigenicity, epitope mapping of this antipeptide antibodies as well- as the polyclonal antibodies to native RCP was undertaken using the Pepscan method. The results reveal that antigenic regions correspond well to conformationally well-defined elements of structure with the polyproline II-like segment being a common antigenic determinant on both the peptide and the native protein. These observations are suggestive of the involvement of both the N and C-terminal regions of RCP in terms of its binding to putative plasma membrane receptors.
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Bayart, Caroline. "Site-specific glycoconjugate synthesis." Thesis, Lyon, 2017. http://www.theses.fr/2017LYSE1267.
Повний текст джерелаАнотація:
Les vaccins conjugués furent développés suite à l’inefficacité des vaccins polysaccharidiques chez les nourrissons et les personnes âgées. Les vaccins conjugués sont composés d’un polysaccharide extrait de la capsule bactérienne et d’une protéine porteuse. Celle-ci permet de décupler la réponse immunitaire, permettant aux vaccins d’être efficaces. L’évolution des connaissances en chimie et en analytique permettent aujourd’hui de mieux caractériser ces vaccins et de mieux maîtriser leur production. Cependant, les chimies de conjugaison utilisées pour lier le polysaccharide et la protéine porteuse, ne sont pas toujours définies et cela mène souvent à l’obtention de produits hétérogènes. Les objectifs de cette thèse ont été d’étudier le polysaccharide, les protéines porteuses et de nouvelles voies de conjugaisons pour lier spécifiquement ces deux biomolécules.Différents outils analytiques ont été utilisés afin d’acquérir une meilleure connaissance des deux partenaires de conjugaison. Cela a également permis d’établir une stratégie d’analyse efficace pour caractériser les produits de réaction. La spécificité des réactions de conjugaison a été induite par l’utilisation d’espaceurs bi-fonctionnels, réagissant spécifiquement sur certains acides aminés. Leur réactivité a d’abord été testée sur un modèle peptidique. Cela a permis de faciliter la caractérisation et d’étudier l’efficacité et la spécificité des réactions. Les réactions efficaces ont ensuite été testées différents modèles : de la protéine au vaccin. Sur les quatre réactions testées, une a été efficace sur tous les modèles. Cette chimie de conjugaison est prometteuse pour le développement de nouveaux vaccinsConjugate vaccines were developed because polysaccharide vaccines were not efficient in infant and old people. These vaccines were composed of the polysaccharide extracted from the bacterial capsule linked to a carrier protein. This protein created an immunological boost which allowed the vaccine to induce a proper protection for everyone. As chemistry knowledge and analytical techniques evolved, vaccines can now be better characterized and the production can be better controlled. Nevertheless, the chemistries used to bind the polysaccharide and the carrier protein are not always well-defined, which leads to the production of heterogeneous products. The objectives of this PhD were to study the polysaccharide, carrier proteins and new conjugation chemistries to specifically bind the two biomolecules. The other challenge was to be able to check the reaction specificity and characterize reaction products.To do so different analytical tools were used to allow a better knowledge of both conjugation partners but also to establish an efficient analytical strategy for glycoconjugate characterization. Conjugation reactions specificity was induced by using different bi-functional linkers, reacting specifically for one type of amino acid. Linkers’ reactivity was first tested on a model peptide. This allowed to facilitate the characterization and to check for both reaction specificity and reaction success. Efficient reactions were then tested on different models from carrier proteins to glycoconjugate vaccines. One of the four tested reactions was efficient from the peptide to the vaccine model. This conjugation is thus promising for the development of new conjugate vaccines
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Le, heiget Guillaume. "Conception de tétrasaccharides orthogonalement protégés, précurseurs d’antigènes représentatifs d’une sélection de sérotypes de shigella flexneri." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCD043.
Повний текст джерелаАнотація:
Les maladies diarrhéiques sont la deuxième cause de mortalité chez les enfants de moins de cinq ans. Les entérobactéries Shigella flexneri sont les principales responsables de la forme endémique de la shigellose, une maladie diarrhéique importante dans les pays en développement et pour laquelle de nombreuses stratégies vaccinales sont à l’étude. La partie polysaccharidique (antigène O, Ag-O) du lipopolysaccharide de surface est l’une des cibles majeures d'immunité protectrice contre la réinfection. Une grande variété d’Ag-Os, reflétant la diversité sérotypique, a été identifiée. De façon intéressante ces Ag-Os se différencient par la nature des substituants portés par le tétrasaccharide ABCD qui définit leur squelette commun. Afin de développer un vaccin issu de sucres de synthèse à large couverture sérotypique contre S. flexneri, des stratégies de synthèse hautement convergente d’analogues orthogonalement protégés du tétrasaccharide ABCD ont été explorées. Elles prennent en compte les sites de -D-glucosylation et de O-acétylation spécifiques de sérotypes. Les approches mises en place s’appuient sur la synthèse d’une diversité de précurseurs en série L-rhamnopyranose et 2-N-acétyl-2-désoxy-D-glucopyranosamine et leurs combinaisons optimisées. Quelques exemples de glucosylation 1,2-cis régiosélective, chimique et/ou enzymatique, valident le conceptDiarrhoeal diseases are the second cause of death among children under five. Shigella flexneri enterobacteria are the main causative agents of the endemic form of shigellosis, a diarrhoeal disease of high prevalence in developing countries and one for which numerous vaccine strategies are under studied. The polysaccharide part (O-antigen, O-Ag) of the bacterial lipopolysaccharide is a major target of protective immunity against reinfection. A large variety of O-Ags, expressing serotypic diversity, has been identified. Interestingly, these O-Ags differ by the nature of the substitutions occurring on the ABCD tetrasaccharide, which defines their common backbone. In order to develop a synthetic carbohydrate-based vaccine with broad serotype coverage against S. flexneri, highly convergent synthetic strategies towards orthogonally protected analogs of tetrasaccharide ABCD were investigated, while taking into account serotype-specific -D-glucosylation and O-acetylation sites. The selected approaches feature the synthesis of a variety of suitable L-rhamnopyranose and 2-N-acetyl-2-deoxy-D-glucopyranosamine precursors and their optimized combinations. The concept is supported by selected examples of 1,2-cis chemical and/or enzymatic glucosylation
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Kow, Daria Karen. "Characterization of avipoxviruses for use in recombinant vaccines." Master's thesis, University of Cape Town, 1992. http://hdl.handle.net/11427/18310.
Повний текст джерелаАнотація:
Pox viruses have been demonstrated in over 60 types of wild and exotic birds as well as domestic birds. Avipox viruses have been isolated and characterised from fowls, quails, canaries, parrots and lovebirds. This work describes the first isolation of a poxvirus from Jackass penguins (Spheniscus dermersus) and the characterisation of the virus as a separate species of penguinpox virus.
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Werts, Kendall (Kendall Marie). "Synthesis of biodegradable hydrogel microparticles for vaccine protein delivery." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/44811.
Повний текст джерелаАнотація:
Thesis (S.B.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2007.Includes bibliographical references (p. 21).
Soluble protein antigens used in vaccines have shown lower immune responses when compared with certain particulate forms of these same antigens. For example, it has been shown that micro- and nano-particle mediated delivery of protein antigen can use up to 100 times less protein and still produce an effective immune response [1]. In order to use this phenomenon to make vaccines more efficient, we need a biodegradable delivery particle. This thesis modifies a particle created by Jain et al., which consists of a polymer network surrounding and trapping a protein, by removing the non-degradable crosslinker used in the original particle design and replacing it with a poly (ethylene glycol) acrylate molecule attached to ovalbumin protein. When a dendritic cell degrades the particle, the ovalbumin protein will be degraded, as will the connections between the polymer network that holds the particle together [2]. The particles degraded to 56% of their original size in 3 days, while the non-degradable particle degraded to only 80% of its original size.
by Kendall Werts.
S.B.
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Ranchod, Heena. "Chemically synthetic mycolic acids as vaccine adjuvants." Diss., University of Pretoria, 2014. http://hdl.handle.net/2263/79305.
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Matthews, Leslie Jeanne. "Synthetic vaccines from peptide libraries : lessons from a model pathogen /." free to MU campus, to others for purchase, 1998. http://wwwlib.umi.com/cr/mo/fullcit?p9924906.
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Chassagne, Pierre. "En route vers des glycoconjugués à potentiel vaccinal contre la dysenterie bacillaire : synthèse d'oligosaccharides représentatifs de l'antigène O de Shigella flexneri sérotype 6." Thesis, Paris 5, 2012. http://www.theses.fr/2012PA05P603.
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Brune, Karl Dietrich. "Engineering modular platforms for rapid vaccine development." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:41d57165-6e7c-4ca7-8025-b5ec31794c8c.
Повний текст джерелаАнотація:
Vaccines have saved more lives than any other medical intervention. Recombinant vaccines provide unmatched safety profiles, but at the expense of reduced immunogenicity. Virus-like particles (VLPs) resemble viruses in size, shape and repetitive arrangement but are devoid of pathogenic genetic material and therefore safe. Poor immunogens can be rendered immunogenic by display on VLPs. Successfully decorating VLPs is still a major challenge. Genetic fusion or chemical modification is often time-consuming and can lead to misassembly or misfolding, which obstructs generation of the desired immune response. SpyCatcher is a genetically encodable protein, previously engineered to form a covalent isopeptide bond to its peptide-partner SpyTag. Presented in this thesis are SpyCatcher-VLPs, based on the fusion of SpyCatcher to the bacteriophage VLP AP205. SpyCatcher- VLPs can be conveniently conjugated with SpyTag fused antigens, simply by mixing. I demonstrate the modularity of this approach by covalently linking several complex, cysteine-rich malarial antigens to SpyCatcher-VLPs, such as the transmission-blocking antigen Pfs25 and the blood-stage antigen CIDR. A single administration of Pfs25-SpyTag conjugated to SpyCatcher-VLPs induced potent antibody generation against Pfs25, even in the absence of adjuvant. Anti-Pfs25 antibodies induced by this platform conveyed potent transmission-blocking activity in the mosquito vector. The thesis further demonstrates the feasibility of more complex Catcher-nanoparticle architectures. The previously engineered SnoopCatcher covalently reacts with SnoopTag peptide and is orthogonal to the SpyCatcher / SpyTag pair. IMX313 is an engineered chimera of the multimerization domain of chicken complement inhibitor C4-binding protein. This work describes fusion of SnoopCatcher and SpyCatcher to IMX313, which yields independently addressable Catcher-moieties on a single IMX313 nanoparticle. Display of two antigens on one particle may enable single-particle, multi-disease vaccines as well as multi-stage vaccines to tackle immune evasion of parasites. The platforms presented should accelerate and enhance vaccine development and may create opportunities for imaging and metabolic engineering.
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Hathaway, Lucy Jane. "Mucosal immunization with synthetic peptides for the systemic and mucosal immune responses." Thesis, London School of Hygiene and Tropical Medicine (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267621.
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Moynihan, Jennifer Susan. "The development of a synthetic hepatitis B vaccine." Thesis, Royal Veterinary College (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392197.
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Miller, Megan Jo. "Novel HER3 and IGF-1R Peptide Mimics and Synthetic Cancer Vaccines." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1408981670.
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Yepuri, Nageshwar Rao. "The design and synthesis of novel anti-malarial agents." Access electronically, 2004. http://www.library.uow.edu.au/adt-NWU/public/adt-NWU20050330.085201/index.html.
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Brand, Elizabeth Gertruida. "Selectable markers for recombinant poxvirus." Thesis, University of Cape Town, 1993. http://hdl.handle.net/11427/25692.
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Jain, Siddhartha Ph D. Massachusetts Institute of Technology. "Synthesis of a hydrogel-based vaccine to mimic dendritic cell responses to pathogens." Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/37957.
Повний текст джерелаАнотація:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2006.Includes bibliographical references (p. 143-160).
Live or attenuated pathogens are the basis of many successful vaccines due in part to the orchestrated response of dendritic cells (DCs) triggered by these immunizations, which includes (1) DC and DC precursor attraction to the immunization site, (2) efficient antigen delivery to class I and class II MHC loading pathways coincident with maturation of DCs, and (3) emigration to draining lymph nodes for T cell activation. We have developed a model immunization system designed to allow these steps in the DC life cycle to be controlled in the context of a subunit vaccine. The system is comprised of microspheres encapsulating chemokines and hydrogel nanoparticles; each nanoparticle contains antigen and DC maturation signals (e.g., TLR ligands). The nanoparticles remain sequestered within the carrier microspheres but the chemokine is released at a controllable rate, creating a local chemoattractant gradient centered on each microsphere. DCs are attracted to individual microspheres where nanoparticles are concentrated; attracted DCs extract nanoparticles from the carrier microspheres, and receive maturation signals coincident with the delivery of antigen into both class I and class II MHC processing pathways.
(cont.) In addition, the nanoparticles may be labeled to allow subsequent tracking of particle-carrying DCs in vivo. These components allow the attraction (or if desired, emigration) of dendritic cells and their precursors to be selectively modulated at an immunization site, and the activation signals received by these cells when they encounter antigen to be tailored. In vitro experiments indicate that chemokine-releasing microspheres effectively attract DCs and monocytes over significant distances, and that the gel nanoparticles efficiently trigger DC maturation and lead to both CD4+ and CD8+ T cell activation in vitro and in vivo. This system provides both a platform for rational immunotherapy as well as a powerful set of tools by which the function of dendritic cells can be manipulated and dissected to improve our understanding of how DC trafficking and functional state impacts immune responses.
by Siddhartha Jain.
Ph.D.
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Bröcker, Felix [Verfasser]. "Towards vaccines and therapeutic antibodies against Clostridium difficile based on synthetic glycans / Felix Bröcker." Berlin : Freie Universität Berlin, 2016. http://d-nb.info/1116344718/34.
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Kinfe, Henok Hadgu. "Progress in the synthesis of stabilized glycoconjugate vaccine candidates against Neisseria meningitides group A." Master's thesis, University of Cape Town, 2003. http://hdl.handle.net/11427/6319.
Повний текст джерелаАнотація:
Includes bibliographical references.Meningitis is the inflammation of the lining membranes of human brains and spinal cord. It is a deadly disease that has claimed millions of lives throughout the world in particular in developing countries. Neisseria meningitidis serogroup A is among the leading causative agents of meningitis in Sub-Saharan Africa. Its capsular polysaccharide antigen consists of a homopolymer of a-(1
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Shi, Mengchao. "Design and Synthesis of a Novel Entirely Carbohydrate-Based Conjugate for Cancer Vaccine Development." University of Toledo / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1470412718.
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Baldwin, Victoria Mae. "Next generation approaches to polysaccharide preparation for Burkholderia pseudomallei vaccine development." Thesis, University of Exeter, 2016. http://hdl.handle.net/10871/30158.
Повний текст джерелаАнотація:
Burkholderia pseudomallei is the aetiological agent of melioidosis and a potential bioterror threat. Infections are difficult to treat due to extensive antibiotic resistance and there is no prophylactic vaccine available. Studies have shown that the capsular polysaccharide (CPS) of B. pseudomallei is a virulence factor, immunogen and candidate antigen for a glycoconjugate vaccine. However, polysaccharides are complex to synthesise. One approach is to genetically engineer Escherichia coli to express the CPS; however, previous attempts at cloning the CPS coding locus from B. pseudomallei into E. coli were unsuccessful. This project proposes to clone only the essential genes from B. pseudomallei and to use native E. coli mechanisms to complete CPS synthesis. This would contribute to development of a new platform for the expression of any bespoke polysaccharide in E. coli. Six biosynthetic genes for the nucleotide sugar precursor were successfully expressed in E. coli. The structure of the precursor was verified by mass spectrometry. Precursor synthesis was also performed in an in vitro microfluidics system. This minimised the quantity of substrates and enzymes required, in preparation for the characterisation of glycosyltransferases required for CPS assembly. A novel assay for characterising glycosyltransferase activity was also developed, as current available options are prohibitively expensive and require significant quantities of glycosyltransferase which are difficult to purify. Finally, plasmids for the expression of additional glycosyltransferases to link the nascent B. pseudomallei CPS to truncated polysaccharides in E. coli were constructed. The aim of this project was to contribute to the development of a platform for the expression of bespoke polysaccharides in E. coli. The CPS of B. pseudomallei was chosen as the model polysaccharide as it has a simple structure and its manufacture is desirable for use in a vaccine against melioidosis.
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Tamborrini, Marco. "Use of synthetic carbohydrates as vaccine components and biomedical research tools /." [S.l.] : [s.n.], 2009. http://edoc.unibas.ch/diss/DissB_8733.
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McGuire, Carolann. "Mucosal vaccination using a crude antigen and a synthetic peptide in the Trichinella spiralis model." Thesis, University of Nottingham, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285567.
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Shen, Dacheng [Verfasser]. "Development of Vaccine Candidates Against Emerging Bacteria via Chemical Syntheses of Antigens / Dacheng Shen." Berlin : Freie Universität Berlin, 2020. http://d-nb.info/1214241182/34.
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Samayoa, Liz. "Evaluating the Immunogenic Potential of Synthetic Influenza T-B & B-T Peptides." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/20575.
Повний текст джерелаАнотація:
Vaccination is one of the major strategies available for combating viral infections in humans. However, currently available vaccines are not without pitfalls; they are laborious to produce, could potentially be unsafe, and in the case of the highly variable influenza virus need to be reformulated each season. The use of synthetic peptides thus represents an exciting alternative to traditional vaccines. However, these synthetic peptides are not highly immunogenic without the use of potent adjuvants. The lack of immunogenicity might be addressed by conjugation between T or B cell epitopes with universal or immunodominant T-helper epitopes. The construction of branched peptides, lipidated peptides, or designs combining both of these elements might also enhance the immunogenicity, as they might target Toll-like receptors and/or mimic the 3-dimensional structure of epitopes within the native protein. In this study, a recognized T-B peptide based on the hemagglutinin protein of the A/Puerto Rico/8/34 influenza virus was chosen as a backbone and modified to evaluate if the construction of branched peptides, lipidation, the addition of cysteine residues, or mutations could indeed alter reactivity. Screening the different designs with various antibody binding and cellular assays revealed that combining a branched design with the addition of lipid moieties leads to a greatly enhanced activity as compared to other similar T-B diepitope constructs.
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Maherzi-Mechalikh, Chahrazed. "Optimisation des vaccins thérapeutiques induisant des réponses T CD8+ spécifiques d’antigènes tumoraux : étude de l’induction des lymphocytes T régulateurs après vaccination." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB035.
Повний текст джерелаАнотація:
La détection de lymphocytes T (LT) CD8+ infiltrant les tumeurs (TIL), est généralement associée à un bon pronostic chez des patients atteints du cancer. A l’inverse, l'infiltration des tumeurs par des LT CD4+ régulateurs (Treg), est quant à elle, souvent corrélée à un mauvais pronostic. Plusieurs vaccins « thérapeutiques » capables d’induire des réponses T CD8+ spécifiques d’antigènes tumoraux ont été développés. Cependant, à ce jour, les résultats cliniques obtenus par ces vaccins restent décevants. Dans un premier travail, nous avons développé puis testé un vaccin thérapeutique composé de trois longs peptides synthétiques (LSP) dérivés de la protéine survivine (SVX). La survivine est une protéine surexprimée dans la majorité des cancers humains, mais absente dans les tissus adultes sains, ce qui fait d’elle une cible thérapeutique privilégiée pour les vaccins anti-tumoraux. Nous avons démontré l'efficacité thérapeutique élevée du vaccin SVX contre diverses tumeurs murines. Ceci a été associé à l'induction de réponses T spécifiques de la survivine, un prolongement de la survie et la génération de réponses mémoires antitumorales. De plus, SVX a induit à la fois des LT CD8+ cytotoxiques spécifiques et LT CD4+ auxiliaires de type 1 multifonctionnelles, dans la rate et au sein des tumeurs. Il a aussi induit une diminution des Treg, favorisant ainsi une réponse immunitaire très efficace. Enfin, une étude préliminaire menée chez des patients atteints de différents types de cancers, nous a révélé la présence de taux élevés de précurseurs spontanés de LT spécifiques du vaccin SVX. Ces résultats suggèrent que SVX pourrait potentiellement stimuler l'activation de ces précurseurs spécifiques. Ces résultats constituent une preuve de concept pour amener ce vaccin comme un produit de première génération en essai clinique chez l’homme. Dans le but d’étudier plus en détails la cinétique des réponses immunitaires T spécifiques, associées aux vaccins LSP, nous avons étudié dans un second travail, l’efficacité d’un vaccin LSP dérivé de la protéine Ovalbumine (OVA). Nous avons montré dans plusieurs modèles de tumeurs murines, que la combinaison du vaccin LSP-OVA à un adjuvant approprié, induisait une forte régression de la croissance tumorale, l’expansion des cellules spécifiques T CD4+ et T CD8+ dans les organes lymphoïdes, ainsi que leur migration vers les tumeurs. De plus, le vaccin a induit des cellules T spécifiques fonctionnelles, comme le témoignent les niveaux élevés de cytokines cytotoxiques mesurées. De manière intéressante, le vaccin n’a pas induit de Treg spécifiques d’OVA ou de Treg polyclonaux et ce, malgré la présence de la tumeur. Enfin, lorsque LSP-OVA ne parvenait pas à induire une régression complète de la tumeur, celle-ci était infiltrée par des TIL CD4+ conventionnels et CD8+ exprimant fortement les récepteurs inhibiteurs (PD-1, TIM-3 et TIGIT). Nos résultats suggèrent que pour optimiser ce vaccin LSP, une association à des anticorps bloquant un ou plusieurs de ces récepteurs inhibiteurs, devrait être envisagéeThe presence of tumor-infiltrating CD8+ T lymphocytes (TIL) is generally associated with a good prognosis in cancer patients. Conversely, the infiltration of tumors by CD4+ regulators T cells (Treg), is often associated with poor prognosis. Several "therapeutic" vaccines able to induce tumor-specific CD8+ T cell responses have been developed. However, to date, the clinical results of these vaccines remain insufficient. In a first work, we developed and analyzed the immunogenicity and therapeutic efficacy of a new survivin vaccine (SVX) composed of three long synthetic peptides (LSP) containing several CD4 and CD8 T-cell epitopes. Survivin is over-expressed by most human cancers, but absent in healthy adult tissues, making it an interesting therapeutic target for cancer vaccines. We demonstrated the high therapeutic efficacy of SVX vaccine against various established murine tumor models, associated with its capacity to generate both specific cytotoxic CD8+ and multifunctional Th1 CD4+ T-cell responses but also effective memory T-cell responses for long-term protection against relapses. Treatment with SVX vaccine was also found to strongly increase the tumor infiltration of both CD4+ and CD8+ T cells over Treg cells therefore tipping the balance toward a highly efficient immune response. Finally, a preliminary study in patients with different types of cancer revealed the presence of high levels of SVX-specific spontaneous T-cell precursors. This suggests that SVX can potentially stimulate the activation of these specific precursors. Altogether, our results strongly suggest that SVX is a promising cancer vaccine and warrants its further clinical development. In order to study the kinetics of tumor-specific immune responses associated with LSP vaccines, we studied the efficacy of a LSP vaccine derived from the Ovalbumin (OVA) protein. We showed in two tumor models that the combination of LSP-OVA with a suitable adjuvant induced a strong tumor regression, an important expansion of both OVA-specific CD4+ and CD8+ T cells in the lymphoid organs, as well as their migration to the tumor. In addition, the vaccine induced functional specific T cells, as shown by the high levels of cytotoxic cytokines. Interestingly, the vaccine did not induce either OVA-specific or polyclonal Treg, despite the presence of the tumor. Finally, when LSP-OVA failed to induce a complete depletion of the tumor, we observed an important expression of inhibitory receptors (PD-1, TIM-3 and TIGIT) on conventional CD4+ and CD8+ TIL. Our results suggest that to optimize this LSP vaccine, a combination with one or more immune checkpoint blockade agents should be considered
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James, Brady Davis. "Synthesis of Functionalized Streptococcus pneumoniae Serotype 6A Di- and Tri- Saccharides." BYU ScholarsArchive, 2020. https://scholarsarchive.byu.edu/etd/8999.
Повний текст джерелаАнотація:
There is a rise in prevalence of antibiotic resistance in Streptococcus pneumoniae, and its FDA-approved vaccines often do not mount effective immune responses in children, the elderly, or the immunocompromised. One reason these vaccines are generally less effective is because they do not utilize T-cell help. T-cell help can be accessed when di-, tri-, or tetra-saccharides positioned inside major histocompatibility complex (MHC) II are presented to T-cell receptors as a target antigen. Pairing MHC II-antigen complexes with T-cell receptors enables development of B and T lymphocytes that are highly specific to these antigens, granting an increase in antibody affinity and cell memory. One problem with today's vaccines against S. pneumoniae, in contrast, is that extracted, polymeric sugars cannot be presented to T-cells by MHC because they do not fit inside the MHC II complex due to their large molecular size. Thus, FDA-approved vaccines generate antibodies which have inadequate affinities and are largely nonspecific in their targets. This thesis covers the synthesis of a functionalized S. pneumoniae serotype 6A disaccharide and trisaccharide, which are core components of the repeating unit of natural capsular polysaccharides, and can be used to obtain necessary T-cell help in working vaccines and good monoclonal antibodies.
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Guichard, Gilles. "Synthese et activite antigenique de pseudopeptides. Implications vaccinales et therapeutiques." Université Louis Pasteur (Strasbourg) (1971-2008), 1996. http://www.theses.fr/1996STR13192.
Повний текст джерелаАнотація:
Le remplacement isostere de la liaison peptidique (conh) est une strategie interessante pour ameliorer la biodisponibilite des peptides d'interet pharmacologique. Elle permet egalement d'introduire localement des changements conformationnels (perturbations geometriques, electroniques et modification du reseau de liaisons hydrogene intra- ou intermoleculaire) et de moduler l'interaction du ligand avec son recepteur. Curieusement, malgre des applications potentielles en vaccination, dans le diagnostic ou en immunomodulation, les pseudopeptides sont restes tres peu utilises dans le domaine de l'immunologie. Dans le travail decrit dans ce memoire, nous nous sommes interesses tout particulierement a la synthese de pseudopeptides reduits ou retro-inverso, analogues de peptides antigeniques impliques dans la reponse humorale ou cellulaire. Dans le cadre de la reponse humorale, nous avons applique avec succes le concept de la retro-enantiomerie a l'hexapeptide c-terminal de l'histone h3 et a l'epitope immunodominant du virus de la fievre aphteuse (fmdv). La decouverte d'un mimetisme antigenique entre le peptide parent et son analogue entierement retro-inverso est prometteuse dans le domaine du diagnostic et dans le developpement de vaccins synthetiques. Nous avons notamment montre, dans le cas du fmdv, que l'immunisation de cobayes avec l'analogue retro-inverso du peptide 141-159 de la proteine virale vp1 permettait d'induire une reponse en anticorps neutralisants plus longue et plus intense, capable de proteger l'animal apres inoculation du virus. Parallelement a ce travail, l'influence de l'incorporation d'une liaison reduite sur les proprietes antigeniques et immunogeniques du peptide modele 130-135 de l'histone h3 a egalement ete etudiee. Dans une deuxieme partie, nous avons synthetise plusieurs series de peptides reduits ou partiellement retro-inverso analogues d'epitopes t cytotoxiques humains ou murins, et determine leur capacite a se lier a la molecule de classe i du complexe majeur d'histocompatibilite correspondante. Les ligands pseudopeptidiques mis en evidence dans cette etude preliminaire ont ensuite ete testes pour leur reconnaissance par des lymphocytes t cytotoxiques specifiques du peptide parent. Dans le cas de l'epitope 58-66 de la proteine matrice du virus de la grippe le profil des cytokines secretees par les cellules t cytotoxiques apres stimulation par le peptide parent ou un analogue partiellement retro-inverso a egalement ete determine et des differences ont pu etre mises en evidence. La possibilite de moduler les fonctions effectrices des cellules t presente non seulement des applications cliniques potentielles pour le traitement de maladies autoimmunes mais pourrait etre interessante pour mieux controler la nature de la reponse immune en fonction de l'agent infectieux et du stade de l'infection
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Marsian, Johanna. "Transient expression of poliovirus-like particles in plants : developing a synthetic polio vaccine." Thesis, University of East Anglia, 2016. https://ueaeprints.uea.ac.uk/62929/.
Повний текст джерелаАнотація:
Plants, or cell suspension cultures derived from them, are a promising platform for the production of biologics and pharmaceuticals. In this work transient expression utilising the pEAQ vector system was deployed for the expression of virus-like particles (VLPs) in Nicotiana benthamiana or N. tabacum BY-2 cell suspension cultures. The results presented in this thesis demonstrate the potential of plant systems for the production of VLP-based vaccines. VLPs of the fish virus, Nervous necrosis virus (NNV), were successfully produced in plants by transient expression of the coat protein. The protein self-assembled into T = 3 particles, which appeared to be morphologically identical to the wild-type NNV when analysed by high resolution microscopy but were devoid of nucleic acid. In addition, transgenic BY-2 cell suspension lines were generated expressing correctly assembled NNV VLPs. Poliovirus (PV)-like particles from all three PV serotypes, containing either the wt coat protein or coat proteins with stabilising mutations, were successfully expressed in plants. These were generated by co-expression of the structural polyprotein P1 and the proteinase 3CD. Sufficient quantities of purified particles could be obtained for structural and immunological analysis. Mice carrying the gene for the human PV receptor were protected from wild-type PV when immunised with the plant-made stabilised PV VLPs. Structural analysis of the stabilised mutant of PV3 at 3.6 Å resolution revealed a structure almost indistinguishable from wild-type PV3, with the stabilising mutations having no effective on the antigenic surface of the particle. To make the product more attractive to the vaccine industry, tobacco BY-2 cells have been successfully tested for the transient expression of the above-mentioned PV mutant VLPs using the cell-pack method.
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Larcombe, L. "Computional selection of synthetic antigens for application in diagnostic, vaccine and therapeutic development." Thesis, Cranfield University, 2006. http://dspace.lib.cranfield.ac.uk/handle/1826/11297.
Повний текст джерелаАнотація:
This work set out to apply computational tools and biophysics principles to develop a
systematic approach to the rational selection of synthetic antigens from appropriate DNA
sequences. The wider potential to the rapid development of diagnostics will be demonstrated
by application towards a chlamydia-specific immunodiagnostic, and the potential for vaccine
and therapeutic development will be discussed.
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Larcombe, Lee. "Computational selection of synthetic antigens for application in diagnostic, vaccine and therapeutic development." Thesis, Cranfield University, 2006. http://dspace.lib.cranfield.ac.uk/handle/1826/11297.
Повний текст джерелаАнотація:
This work set out to apply computational tools and biophysics principles to develop a systematic approach to the rational selection of synthetic antigens from appropriate DNA sequences. The wider potential to the rapid development of diagnostics will be demonstrated by application towards a chlamydia-specific immunodiagnostic, and the potential for vaccine and therapeutic development will be discussed.
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Steinbeis, Fridolin [Verfasser]. "Protective potential and immunological evaluation of synthetic Plasmodium GPI glycoconjugate vaccines against experimental cerebral malaria / Fridolin Steinbeis." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2017. http://d-nb.info/1133492908/34.
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Martin, Christopher E. [Verfasser]. "Chemical Synthesis and Biological Evaluation of Cell Surface Carbohydrate Antigens for Rational Vaccine Design / Christopher E. Martin." Berlin : Freie Universität Berlin, 2016. http://d-nb.info/1081935537/34.
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Sella, Mauro [Verfasser]. "Chemical synthesis of oligosaccharide antigens as vaccine candidates for Streptococcus suis serotypes 2 and 14 / Mauro Sella." Berlin : Freie Universität Berlin, 2021. http://d-nb.info/1228334579/34.
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Smith, Mark T. "Engineering Cell-Free Systems for Vaccine Development, Self-Assembling Nanoparticles and Codon Reassignment Applications." BYU ScholarsArchive, 2014. https://scholarsarchive.byu.edu/etd/4449.
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This dissertation reports on the technology of cell-free protein synthesis (CFPS) including 1) stabilized lyophilized cell-free systems and 2) enhanced heterogeneous cell extracts. This work further considers applications of CFPS systems in 1) rapid vaccine development, 2) functional virus-based nanoparticles, 3) site-specific protein immobilization, and 4) expanding the language of biology using unnatural amino acids. CFPS technology is a versatile protein production platform that has many features unavailable in in vivo expression systems. The primary benefit cell-free systems provide is the direct access to the reaction environment, which is no longer hindered by the presence of a cell-wall. The “openness” of the system makes it a compelling candidate for many technologies. One limitation of CFPS is the necessity of freezing for long-term viable storage. We demonstrate that a lyophilized CFPS system is more stable against nonideal storage than traditional CFPS reagents. The Escherichia coli-based CFPS system in this work is limited by the biocatalytic machinery found natively in E. coli. To combat these limitations, exogenous biocatalysts can be expressed during fermentation of cells prepared into extract. We demonstrate that simple adjustments in the fermentation conditions can significantly increase the activity of the heterogeneous extract. Towards virus-based particles and vaccines, we demonstrate that the open nature of CFPS can be utilized for coexpression of virus proteins and self-assembly of virus particles. This technique allows for the rapid production of potential vaccines and novel functional virus-based nanoparticles. Unnatural amino acids expand the effective language of protein biology. Utilizing CFPS as an expression system, we demonstrated that the incorporation of a single specific unnatural amino acid allows for site-specific immobilization, thus stabilizing the protein against elevated temperatures and chemical denaturants. Current unnatural amino acid incorporation technologies are limited to one or few simultaneous incorporations and suffer from low efficiency. This work proposes a system that could potentially allow for upwards of 40 unnatural amino acids to be simultaneously incorporated, effectively tripling the protein code. These projects demonstrate the power and versatility of CFPS technologies while laying the foundation for promising technologies in the field of biotechnology.
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Grässlin, Anja. "Protein epitope mimetics as inhibitors of protein-protein interactions and in synthetic vaccine design /." Zürich, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000254199.
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Kleski, Kristopher A. "Progress of Entirely Carbohydrate Conjugates in Cancer Immunotherapeutics – Syntheses and Developments." University of Toledo / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1586980386810219.
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Murdin, A. D. "Studies of aphthovirus subunits and synthetic peptides relevant to their use as vaccines against foot and mouth disease." Thesis, University of Surrey, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.370712.
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Souza, Aline Rubens de, and 92-98135-6034. "Avaliação do potencial vacinal de peptídeos de antígenos de Shigella spp." Universidade Federal do Amazonas, 2018. https://tede.ufam.edu.br/handle/tede/6691.
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FAPEAM - Fundação de Amparo à Pesquisa do Estado do Amazonas
Shigellosis is a diarrheal disease that mainly affects children under 5, caused by a Gram-negative and enteroinvasive bacterium called Shigella. Mice are among the most commonly used animal models for assessing the immune response of this pathogen, due to their similarity to intestinal responses when they are subjected to infection. As no shigellosis vaccine is available yet, synthetic peptide vaccines are proposed as an alternative, which are produced from amino acid sequences of bacterial proteins and are synthesized in the laboratory. Thus, this study aimed to immunize mice from the BALB/c line through the intraperitoneal route with synthetic peptides that were designed from immunodominant epitopes of the outer membrane surface proteins of Shigella spp., called OmpC, OmpA and FimH, and then subjected them to challenge infection with a lethal dose of a virulent bacterial strain - S. flexneri 5a M90T, to estimate the protective capacity of the peptides, thus simulating the idea of a vaccine. The production of anti-peptide antibodies was analyzed by means of the Indirect ELISA immunoenzymatic assay, and the evaluation of the recognition of these antibodies in the native proteins present in the Shigella species was performed by Flow Cytometry. After challenge infection, the mice were observed for weight and survival, and the post-challenge cytokine secretion pattern was assessed by CBA (Cytometric Bead Array). The results demonstrated that all groups of peptides tested showed to be immunogenic in the first step of immunization with them in mice, as well as recognition of the antibodies in S. flexneri, S. boydii and S. dysenteriae proteins before and after challenge with M90T. All mice belonging to the selected peptide groups survived after the challenging infection, but the mice in the Peptide 1 and Pool- groups did not recover the initial weight. The peptide 2 group stood out among the others in the evaluation of the post-challenge cytokines by the equilibrium observed among them, thus suggesting a regulation of the immune system of the mice. Thus, among all the peptides tested in this study, P2 is indicated as the most effective in the intraperitoneal route, because it has been shown to be both immunogenic and an effective protector in Shigella infection, which favors it being a good vaccine candidate for shigellosis.
Shigelose é uma doença diarreica que afeta principalmente crianças menores de 5 anos, causada por uma bactéria Gram-negativa e enteroinvasiva denominada Shigella. Os camundongos estão entre os modelos de animais utilizados mais comuns para avaliação da resposta imune desse patógeno, devido sua similaridade com as respostas intestinais quando são submetidos à infecção. Como não está disponível ainda nenhuma vacina contra shigelose, propõe-se como alternativa as vacinas de peptídeos sintéticos, que são produzidas a partir de sequências de aminoácidos de proteínas da bactéria e são sintetizadas em laboratório. Assim, este estudo objetivou imunizar camundongos da linhagem BALB/c pela via intraperitoneal com peptídeos sintéticos que foram desenhados a partir de epítopos imunodominantes das proteínas de superfície da membrana externa de Shigella spp., denominadas OmpC, OmpA e FimH, e posteriormente submetê-los a infecção desafio com uma dose letal de uma cepa virulenta da bactéria – a S. flexneri 5a M90T, para estimar a capacidade de proteção dos peptídeos, simulando assim a idéia de uma vacina. A produção de anticorpos anti-peptídeos foi analisada por meio do teste imunoenzimático ELISA Indireto, e a avaliação do reconhecimento desses anticorpos nas proteínas nativas presentes nas espécies de Shigella foi realizada por Citometria de Fluxo. Após a infecção desafio, os camundongos foram observados em relação ao peso e sobrevivência, e o padrão de secreção de citocinas pós-desafio foi avaliado por CBA (Cytometric Bead Array). Os resultados demonstraram que todos os grupos de peptídeos testados demonstraram ser imunogênicos na primeira etapa de imunização com eles nos camundongos, assim como houve reconhecimento dos anticorpos nas proteínas de S. flexneri, S. boydii e S. dysenteriae antes e após o desafio com a M90T. Todos os camundongos pertencentes aos grupos de peptídeos selecionados sobreviveram após a infecção desafio, porém os camundongos dos grupos do peptídeo 1 e do Pool- não conseguiram a recuperação do peso inicial. O grupo do peptídeo 2 se destacou entre os demais na avaliação das citocinas pós-desafio pelo equilíbrio observado entre elas, sugerindo assim uma regulação do sistema imune dos camundongos. Assim, entre todos os peptídeos testados neste trabalho, indica-se o P2 como o mais efetivo na via intraperitoneal, por ter demonstrado ser tanto imunogênico como um protetor eficaz na infecção por Shigella, o que favorece que ele seja um bom candidato vacinal para shigelose.
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Cotton, Graham J. "Studies on synthetic peptides from HIV-1 gp120 for the development of an AIDS vaccine." Thesis, University of Edinburgh, 1994. http://hdl.handle.net/1842/13477.
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The design and synthesis of discontinuous epitopes of HIV-1 gp120 has been investigated. This has been exemplified by the design of a peptide to mimic a discontinuous but conserved region of gp120 containing residues important for CD4 binding. This peptide was synthesised using the Fmoc strategy of solid phase peptide synthesis. The problem of aspartimide formation as a side product in the synthesis was observed and this process was addressed in more detail. Polyclonal antisera were raised in mice against the purified peptide and the antipeptide antibodies characterised. Initial evidence suggests this peptide binds to CD4 and induces apoptosis.
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Schumann, Benjamin [Verfasser]. "Synthesis and Immunological Evaluation of Oligosaccharide-Antigens as Vaccine Candidates for Streptococcus pneumoniae Serotypes 1 and 8 / Benjamin Schumann." Berlin : Freie Universität Berlin, 2015. http://d-nb.info/1080522093/34.
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Schutze, Marie-Paule. "Suppression epitopique et vaccins synthetiques : evidences, mecanismes et alternatives." Paris 6, 1987. http://www.theses.fr/1987PA066619.
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